CN115181120A - Preparation method of 2-methyl-3-phenyl styryl pinacol borate - Google Patents
Preparation method of 2-methyl-3-phenyl styryl pinacol borate Download PDFInfo
- Publication number
- CN115181120A CN115181120A CN202210874329.5A CN202210874329A CN115181120A CN 115181120 A CN115181120 A CN 115181120A CN 202210874329 A CN202210874329 A CN 202210874329A CN 115181120 A CN115181120 A CN 115181120A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- methyl
- argon
- cooling
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- -1 styryl pinacol borate Chemical compound 0.000 title claims description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 95
- 239000002994 raw material Substances 0.000 claims abstract description 10
- BGTLHJPGBIVQLJ-UHFFFAOYSA-N (2-methyl-3-phenylphenyl)methanol Chemical group CC1=C(CO)C=CC=C1C1=CC=CC=C1 BGTLHJPGBIVQLJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 46
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 229910052786 argon Inorganic materials 0.000 claims description 35
- 239000000047 product Substances 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 27
- 238000002390 rotary evaporation Methods 0.000 claims description 26
- 238000001816 cooling Methods 0.000 claims description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 239000003208 petroleum Substances 0.000 claims description 23
- 239000012074 organic phase Substances 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 12
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 230000005587 bubbling Effects 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 7
- 235000011056 potassium acetate Nutrition 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 6
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 238000010926 purge Methods 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000002386 leaching Methods 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000006392 deoxygenation reaction Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 claims 1
- 238000007792 addition Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000010924 continuous production Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 abstract 1
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 230000009467 reduction Effects 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 3
- 239000010779 crude oil Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 102000008096 B7-H1 Antigen Human genes 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091007744 Programmed cell death receptors Proteins 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of 2-methyl-3-phenyl styryl boronic acid pinacol ester. The invention takes 3-hydroxymethyl-2-methyl biphenyl as raw material, and 2-methyl-3-phenyl styryl boric acid pinacol ester is prepared through a series of reactions such as oxidation, addition, bromination, reduction, dehydration and the like. The product obtained by the invention has high trans-form proportion, is easy to purify, and can provide products with different E/Z proportions from 90% to 99%; the production raw materials are conventional bulk raw materials, are easy to obtain and are suitable for large-scale continuous production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of 2-methyl-3-phenyl styryl boronic acid pinacol ester.
Background
PD-1 (programmed death receptor 1), an important immunosuppressive factor. The immunoregulation taking PD-1 as a target has important significance for resisting tumor, infection and autoimmune diseases, organ survival and the like. The ligand PD-L1 can also be used as a target point, and the corresponding antibody can also play the same role.
Currently, the marketed PD-1/PD-L1 antibody inhibitors include Nivolomab, atezolizumab and the like, which are all biological macromolecules, while small-molecular PD-1/PD-L1 inhibitors are in the development stage. Compared with biological macromolecules, the micromolecules have wider application range, good bioavailability and compliance, and are more mature in the aspects of production, drug combination and the like.
In the prior art, reports that biphenyl compound small molecule PD-1/PD-L1 inhibitors are successfully listed do not appear, and an important intermediate 2-methyl-3-phenyl styryl boronic acid pinacol ester is rarely reported.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of 2-methyl-3-phenyl styryl pinacol borate.
The invention relates to a preparation method of 2-methyl-3-phenyl styryl pinacol borate, which comprises the following reaction routes:
comprises the following steps of (a) preparing a solution,
(1) Adding 3-hydroxymethyl-2-methyl biphenyl and dichloromethane into a reaction kettle, keeping the temperature at 20-25 ℃, adding active manganese dioxide in batches, filtering to remove manganese dioxide after the raw materials completely react, and carrying out rotary evaporation and drying on the filtrate to obtain a compound I;
(2) Putting a compound I and anhydrous dichloromethane into a reaction kettle, replacing twice with argon, cooling to-5-5 ℃, slowly dropwise adding a methyl magnesium chloride solution, controlling the temperature to be 0-20 ℃, after the reaction is completed, controlling the temperature to be 0-20 ℃, dropwise adding dilute hydrochloric acid to quench the reaction, acidifying until the pH is =2-3, and extracting a water phase with dichloromethane; combining organic phases, washing with water, drying, evaporating to remove the solvent, and drying in vacuum to obtain a compound II;
(3) Mixing dichloromethane and the compound II under stirring, heating to reflux, and adding manganese dioxide in batches; after the reaction is finished, cooling, suction filtering, leaching filter cakes, concentrating the organic phase under reduced pressure to dryness, adding petroleum ether, stirring, cooling to 0-5 ℃, suction filtering, and drying to obtain a compound III;
(4) Under the protection of argon, adding the compound III, methanol and silica gel into a reaction bottle, heating to 50-55 ℃, adding NBS in batches, and controlling the reaction to be in a micro-reflux state; after NBS is added, the reaction is finished, the temperature is reduced to room temperature, methanol is removed through rotary evaporation, dichloromethane is added into residues, the residues are stirred and dispersed, filtration and leaching are carried out, filter cakes are abandoned, filtrate is dried through rotation to obtain oily crude products, and the crude products are purified through column chromatography to obtain a compound IV; preferably, after the first batch of NBS is added and the temperature is raised to micro-reflux, the LED light source initiates a reaction; the residual NBS is added in 10-20 batches, and the reaction is always controlled to be in a micro-reflux state;
(5) Under the protection of argon, adding a compound IV and methanol into a reaction bottle, cooling to 0-5 ℃, adding sodium borohydride in batches, and controlling the process temperature to 0-15 ℃; after the reaction is finished, pouring the reaction liquid into water, adjusting the pH value to be 5-6 by hydrochloric acid, and removing methanol by rotary evaporation; then extracting with ethyl acetate, combining organic phases, washing with saturated sodium bicarbonate, drying with anhydrous sodium sulfate, removing ethyl acetate by rotary evaporation, stirring and dispersing n-heptane, performing suction filtration, and performing vacuum drying at room temperature to obtain a compound V;
(6) Under the protection of argon, adding a compound V, p-toluenesulfonic acid monohydrate and anhydrous toluene into a reaction bottle, performing reflux reaction, completely reacting, cooling, washing an organic phase with a saturated sodium bicarbonate aqueous solution to neutrality, performing rotary evaporation to remove toluene, performing negative-pressure rapid column chromatography purification, adding petroleum ether into the mixture after evaporation, performing dispersive crystallization at 0-5 ℃, performing suction filtration, and performing vacuum drying at room temperature to obtain a compound VI;
(7) Purging and replacing argon in a reaction bottle, then sequentially adding a compound VI, anhydrous dioxane, polyboronate pinacol ester and anhydrous potassium acetate, and then introducing an argon pipe below the liquid level for bubbling and deoxidizing; then Pd (dppf) Cl is added 2 -CH 2 Cl 2 Continuously bubbling for deoxidizing; and after deoxygenation is finished, protecting the reaction system by using an argon ball, heating to the internal temperature of 85-90 ℃ for reaction, cooling after the reaction is finished, removing dioxane by rotary evaporation, adding petroleum ether, stirring and dispersing, combining the petroleum ether phases, evaporating to dryness, and purifying by using column chromatography to obtain the product.
In the step (1), in terms of molar ratio, 3-hydroxymethyl-2-methylbiphenyl: active manganese dioxide = 1.
In step (2), compound I: methyl magnesium chloride = 1.1-1.2.
In step (3), compound II: active manganese dioxide = 1.
In the step (3), the time interval between two adjacent batches of active manganese dioxide is 4-5h.
In step (4), compound III: NBS = 1-1.5.
In step (5), compound IV: sodium borohydride = 1.
In step (6), compound V: p-toluenesulfonic acid monohydrate =1, 0.1-0.3.
In step (7), compound VI: pinacol ester diboron: anhydrous potassium acetate: pd (dppf) Cl 2 -CH 2 Cl 2 ＝1:3:3:0.03。
The product obtained by the invention has high trans-form proportion, is easy to purify, and can provide products with different E/Z proportions from 90% to 99%; the production raw materials are conventional bulk raw materials which are easy to obtain, and the method is suitable for amplification, can be used for continuous production, provides ton-grade products and has considerable economic benefit.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the 2-methyl-3-phenylstyrene pinacol borate of the present invention.
Detailed Description
Example 1
A preparation method of 2-methyl-3-phenylstyryl pinacol borate comprises the following steps:
(1) Adding 1kg of 3-hydroxymethyl-2-methyl biphenyl and 10L of dichloromethane into a 20L reaction kettle, maintaining the water bath at 20 ℃, adding 3kg of active manganese dioxide in batches within 24h, and filtering to remove the manganese dioxide after the raw materials are completely reacted. The filtrate was rotary evaporated and vacuum dried at room temperature to obtain 960g of off-white solid powder (compound I) with a yield of 96%.
(2) 960g of the product obtained in the above step and 10L of anhydrous dichloromethane were put into a 20L reaction kettle and replaced with argon twice. Cooling the reaction liquid to-5 ℃ in a chilled salt bath, then slowly adding 1.8L of 3M methyl magnesium chloride solution dropwise, controlling the temperature to be 0 ℃, after the reaction is completed, controlling the temperature to be 5 ℃, adding 3M dilute hydrochloric acid dropwise to carry out quenching reaction, acidifying to pH =2, and extracting the water phase twice by using dichloromethane. The organic phases are combined, washed once with saturated salt solution, dried by anhydrous sodium sulfate, evaporated to remove the solvent and dried in vacuum to obtain 1030g of a white-like solid product (compound II) with the yield of 99.1 percent.
(3) 2.2L of dichloromethane were added with mechanical stirring, and 231g of the product obtained in the previous step were placed in a 5L three-necked reaction flask and heated to reflux in an oil bath. 870g of manganese dioxide were then added in portions, with an interval of 5h, and the reaction was terminated for 36 h. After the reaction is finished, cooling and suction filtration are carried out, filter cakes are soaked and washed by 2L dichloromethane, organic phase is concentrated to be dry under the pressure, 300ml petroleum ether is added, stirring is carried out, the temperature is reduced to 0 ℃, suction filtration is carried out to obtain off-white solid, and the product (compound III) 198g is obtained after vacuum drying at room temperature, and the yield is 94.3%.
(4) Under the protection of argon, 172g of the product obtained in the previous step, 2580ml of methanol and 6.3g of silica gel are put into a 3L reaction bottle and heated to 52 ℃. And then adding NBS in batches, heating the mixture in the first batch until micro reflux, and initiating a reaction by using an LED light source. 10% was added to each batch, and the reaction was controlled to a slightly refluxed state. The total addition of 175gNBS was complete. Cooling to room temperature, and removing the methanol by rotary evaporation. The residue is dispersed with stirring by adding 500ml of dichloromethane, rinsed by filtration and the filter cake is discarded. The filtrate was spin dried to give 250g of crude oil, which was purified by column chromatography (n-heptane/ethyl acetate =100% → 95%) to give 212g of purified product (compound IV) in 89.5% yield.
(5) Under the protection of argon, 200g of the product obtained in the previous step and 1L of methanol are put into a 2L three-mouth reaction bottle, the temperature of an ice salt bath is reduced to 0 ℃, 14g of sodium borohydride is added in batches, and the process is controlled within 10 ℃. After the reaction was completed, the reaction solution was poured into 1.5L of water, pH was adjusted to 5 with 6M hydrochloric acid, and methanol was removed by rotary evaporation. Then the aqueous phase is extracted with ethyl acetate for 2 times, the organic phases are combined, 100ml of saturated sodium bicarbonate is washed once, dried by anhydrous sodium sulfate, the ethyl acetate is removed by rotary evaporation, 500ml of n-heptane is stirred for dispersion, filtered by suction, and dried in vacuum at room temperature to obtain 176g of the product (compound V) with the yield of 87.6 percent.
(6) And (3) putting 58.2g of the product obtained in the previous step, 3.8g of p-toluenesulfonic acid monohydrate and 580ml of anhydrous toluene in a 1L three-mouth reaction bottle under the protection of argon, carrying out reflux reaction on the mixture by oil bath families, and reacting completely for 12 hours. The temperature was reduced, 100ml of 2 saturated aqueous sodium bicarbonate solution washed the organic phase to neutrality, and toluene was removed by rotary evaporation. Then purifying by negative pressure flash column chromatography (eluting with pure petroleum ether), evaporating to dryness, adding 116ml petroleum ether, dispersing and crystallizing at 0 ℃, filtering, and vacuum drying at room temperature to obtain 40.4g of white solid (compound VI) with yield of 74%, E: Z =96.4:3.6.
(7) Argon purging and replacing the three-mouth reaction bottle, then sequentially adding 10.7g of the product obtained in the previous step, 107ml of anhydrous dioxane, 30.1g of pinacol diboron and 11.5g of anhydrous potassium acetate, and then introducing an argon pipe below the liquid level for bubbling and deoxidizing for 15min. Then adding Pd (dppf) Cl 2 -CH 2 Cl 2 1g, and continuously bubbling and deoxidizing for 5min. After the deoxidization is finished, the argon ball protects the reaction system, and the reaction system is heated to the internal temperature of 88 ℃ for 2.5h. And (3) cooling after the reaction is finished, removing dioxane by rotary evaporation, adding 200ml × 2 petroleum ether, stirring and dispersing twice, combining petroleum ether phases, evaporating to dryness, and purifying by column chromatography (PE/EA =100% → 50%) to obtain 7.5g of a yellow oily product with the yield of 60%.
Example 2
A preparation method of 2-methyl-3-phenylstyryl pinacol borate comprises the following steps:
(1) Adding 1kg of 3-hydroxymethyl-2-methyl biphenyl and 10L of dichloromethane into a 20L reaction kettle, maintaining a water bath at 25 ℃, adding 4.39kg of active manganese dioxide in batches within 24h, and filtering to remove the manganese dioxide after the raw materials are completely reacted. The filtrate was rotary evaporated and dried under vacuum at room temperature to obtain 956g of off-white solid powder (Compound I) with a yield of 95.6%.
(2) 960g of the product obtained in the above step and 10L of anhydrous dichloromethane were put into a 20L reaction kettle and replaced with argon twice. Cooling the reaction liquid to 0 ℃ by using a iced salt bath, then slowly dropwise adding 1.9L of 3M methyl magnesium chloride solution, controlling the temperature to be 10 ℃, after the reaction is completed, controlling the temperature to be 10 ℃, dropwise adding 3M dilute hydrochloric acid to quench the reaction, acidifying to pH =3, and extracting the water phase twice by using dichloromethane. The organic phases are combined, washed once with saturated salt, dried by anhydrous sodium sulfate, the solvent is removed by rotary evaporation, and the white-like solid product (compound II) 1032g is obtained after vacuum drying, with the yield of 99.3%.
(3) 2.5L of dichloromethane were added with mechanical stirring, and 231g of the product obtained in the above step were placed in a 5L three-necked reaction flask and heated to reflux in an oil bath. 904g of manganese dioxide was then added in portions, with a 4.5h interval, and the reaction was terminated for 36 h. After the reaction is finished, cooling and suction filtration are carried out, a filter cake is soaked and washed by 2L of dichloromethane, the organic phase is concentrated to be dry under the pressure, 300ml of petroleum ether is added, stirring and cooling are carried out to 5 ℃, suction filtration is carried out to obtain a white-like solid, and room temperature vacuum drying is carried out to obtain 199.9g of a product (compound III), and the yield is 95.2%.
(4) Under the protection of argon, 172g of the product obtained in the previous step, 2580ml of methanol and 6.3g of silica gel are put into a 3L reaction bottle and heated to 55 ℃. And then adding NBS in batches, heating the first batch to micro reflux, and then initiating a reaction by an LED light source. 10% was added to each batch, and the reaction was controlled to a slightly refluxed state. The total addition of 146gNBS was complete. And cooling to room temperature, and performing rotary evaporation to remove the methanol. The residue is dispersed with stirring by adding 500ml of dichloromethane, rinsed by filtration and the filter cake is discarded. The filtrate was spin-dried to give 250g of crude oil, which was purified by column chromatography (n-heptane/ethyl acetate =100% → 95%) to give 210.6g of pure product (compound IV) with 88.9% yield.
(5) Under the protection of argon, 200g of the product obtained in the previous step and 1L of methanol are put into a 2L three-mouth reaction bottle, the temperature of an ice salt bath is reduced to 5 ℃, then 13.2g of sodium borohydride is added in batches, and the process is controlled within 15 ℃. After the reaction was completed, the reaction solution was poured into 1.5L of water, pH =6 was adjusted with 6M hydrochloric acid, and methanol was removed by rotary evaporation. The aqueous phase was then extracted 2 times with ethyl acetate (500ml x 2), the organic phases were combined, washed once with 100ml saturated sodium bicarbonate, dried over anhydrous sodium sulfate, rotary evaporated to remove ethyl acetate, stirred and dispersed in 500ml n-heptane, filtered off with suction, and dried under vacuum at room temperature to give 177.4g of product (compound V) in 88.3% yield.
(6) And (3) putting 58.2g of the product obtained in the previous step, 7.6g of paratoluenesulfonic acid monohydrate and 580ml of anhydrous toluene in a 1L three-opening reaction bottle under the protection of argon, carrying out oil bath on the mixture, carrying out reflux reaction on family members, and completing the reaction for 12 hours. The temperature was reduced, 100ml of 2 saturated aqueous sodium bicarbonate solution washed the organic phase to neutrality, and toluene was removed by rotary evaporation. Then purifying by negative pressure flash column chromatography (eluting with pure petroleum ether), evaporating to dryness, adding 116ml petroleum ether, dispersing and crystallizing at 5 ℃, filtering, and vacuum drying at room temperature to obtain 39g of white solid (compound VI) with the yield of 72%, E: Z =96.2:3.8.
(7) Argon purging and replacing the three-mouth reaction bottle, then sequentially adding 10.7g of the product obtained in the previous step, 107ml of anhydrous dioxane, 30.1g of pinacol diboron and 11.5g of anhydrous potassium acetate, and then introducing an argon pipe below the liquid level for bubbling and deoxidizing for 15min. Then adding Pd (dppf) Cl 2 -CH 2 Cl 2 1g, and continuously bubbling and deoxidizing for 5min. After the deoxidization is finished, the argon ball protects the reaction system, and the reaction system is heated to the internal temperature of 85 ℃ for reaction for 2.5h. And (3) cooling after the reaction is finished, removing dioxane by rotary evaporation, adding 200ml × 2 petroleum ether, stirring and dispersing twice, combining petroleum ether phases, evaporating to dryness, and purifying by column chromatography (PE/EA =100% → 50%) to obtain 7.75g of a yellow oily product with the yield of 62%.
Example 3
A preparation method of 2-methyl-3-phenylstyryl pinacol borate comprises the following steps:
(1) Adding 1kg of 3-hydroxymethyl-2-methyl biphenyl and 10L of dichloromethane into a 20L reaction kettle, maintaining the water bath at 20 ℃, adding 2.20kg of active manganese dioxide in batches within 24 hours, and filtering to remove the manganese dioxide after the raw materials completely react. The filtrate was rotary evaporated and dried under vacuum at room temperature to give 955g of off-white solid powder (Compound I) in 95.5% yield.
(2) 960g of the product obtained in the previous step and 10L of anhydrous dichloromethane are put into a 20L reaction kettle and replaced by argon twice. And cooling the reaction liquid to 5 ℃ in a chilled salt bath, then slowly adding 1.8L of 3M methyl magnesium chloride solution dropwise, controlling the temperature to be 20 ℃, after the reaction is completed, controlling the temperature to be 20 ℃, adding 3M dilute hydrochloric acid dropwise to quench the reaction, acidifying to pH =2, and extracting the water phase twice by using dichloromethane. The organic phases are combined, washed once with saturated salt solution, dried by anhydrous sodium sulfate, evaporated to remove the solvent and dried in vacuum to obtain 1024g of a white-like solid product (compound II) with the yield of 98.6 percent.
(3) 2.2L of dichloromethane were added with mechanical stirring, and 231g of the product obtained in the previous step were placed in a 5L three-necked reaction flask and heated to reflux in an oil bath. 947g of manganese dioxide are then added in portions, the reaction time being 4h, and the reaction time being about 36 h. After the reaction is finished, cooling and suction filtration are carried out, filter cakes are soaked and washed by 2L dichloromethane, organic phase is concentrated to be dry under the pressure, 300ml petroleum ether is added, stirring is carried out, the temperature is reduced to 5 ℃, suction filtration is carried out to obtain off-white solid, and the product (compound III) is dried in vacuum at room temperature to obtain 201.8g, and the yield is 96.1%.
(4) Under the protection of argon, 172g of the product obtained in the previous step, 2580ml of methanol and 6.3g of silica gel are put into a 3L reaction bottle and heated to 50 ℃. And then adding NBS in batches, heating the first batch to micro reflux, and then initiating a reaction by an LED light source. 10% was added to each batch and the reaction was controlled at slightly reflux. The total addition of 175gNBS was complete. Cooling to room temperature, and removing the methanol by rotary evaporation. The residue is dispersed with stirring by adding 500ml of dichloromethane, rinsed by filtration and the filter cake is discarded. The filtrate was spin-dried to give 250g of crude oil, which was purified by column chromatography (n-heptane/ethyl acetate =100% → 95%) to give 201.8g of pure product (compound IV) in 89.3% yield.
(5) Under the protection of argon, 200g of the product obtained in the previous step and 1L of methanol are put into a 2L three-mouth reaction bottle, the temperature of an ice salt bath is reduced to 0 ℃, and then 13.6g of sodium borohydride is added in batches, and the process is controlled within 5 ℃. After the reaction was completed, the reaction solution was poured into 1.5L of water, pH =5 was adjusted with 6M hydrochloric acid, and methanol was removed by rotary evaporation. Then the aqueous phase was extracted 2 times with ethyl acetate, the organic phases were combined, washed once with 100ml of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, rotary evaporated to remove ethyl acetate, stirred and dispersed with 500ml of n-heptane, filtered with suction, and vacuum dried at room temperature to obtain 175.4g of the product (compound V) with a yield of 87.3%.
(6) And (3) putting 58.2g of the product obtained in the previous step, 11.4g of p-toluenesulfonic acid monohydrate and 580ml of anhydrous toluene in a 1L three-mouth reaction bottle under the protection of argon, carrying out reflux reaction on the mixture by oil bath families, and reacting completely for 12 hours. The temperature was reduced, 100ml of 2 saturated aqueous sodium bicarbonate solution washed the organic phase to neutrality, and toluene was removed by rotary evaporation. Then purifying by negative pressure flash column chromatography (eluting with pure petroleum ether), evaporating to dryness, adding 116ml petroleum ether, dispersing and crystallizing at 0 ℃, filtering, and vacuum drying at room temperature to obtain 41g of white solid (compound VI), wherein the yield is 75.2%, E: Z =96.5:3.5.
(7) Argon purging and replacing the three-opening reaction bottle, then sequentially adding 10.7g of the product obtained in the previous step, 107ml of anhydrous dioxane, 30.1g of pinacol diboron diboride and 11.5g of anhydrous potassium acetate, and then introducing an argon pipe below the liquid level for bubbling and deoxidizing for 15min. Then adding Pd (dppf) Cl 2 -CH 2 Cl 2 1g, and continuously bubbling and deoxidizing for 5min. After the deoxidization is finished, the argon ball protects the reaction system, and the reaction system is heated to the internal temperature of 90 ℃ for 2.5h. And (3) cooling after the reaction is finished, removing dioxane by rotary evaporation, adding 200ml × 2 petroleum ether, stirring and dispersing twice, combining petroleum ether phases, evaporating to dryness, and purifying by column chromatography (PE/EA =100% → 50%) to obtain 7.67g of a yellow oily product with the yield of 61.3%.
Claims (10)
1. A preparation method of 2-methyl-3-phenyl styryl pinacol borate is characterized in that the reaction route is as follows:
2. the process for producing 2-methyl-3-phenylstyrylboronic pinacol ester according to claim 1, which comprises the steps of,
(1) Adding 3-hydroxymethyl-2-methyl biphenyl and dichloromethane into a reaction kettle, keeping the temperature at 20-25 ℃, adding active manganese dioxide in batches, filtering to remove manganese dioxide after the raw materials completely react, and carrying out rotary evaporation and drying on the filtrate to obtain a compound I;
(2) Putting a compound I and anhydrous dichloromethane into a reaction kettle, replacing twice with argon, cooling to-5-5 ℃, slowly adding a methyl magnesium chloride solution dropwise, controlling the temperature to be 0-20 ℃ after the reaction is completed, adding dilute hydrochloric acid dropwise to quench the reaction, acidifying until the pH is =2-3, and extracting a water phase with dichloromethane; combining organic phases, washing with water, drying, evaporating to remove the solvent, and drying in vacuum to obtain a compound II;
(3) Mixing dichloromethane and the compound II under stirring, heating to reflux, and adding active manganese dioxide in batches; after the reaction is finished, cooling, suction filtering, leaching filter cakes, concentrating the organic phase under reduced pressure to dryness, adding petroleum ether, stirring, cooling to 0-5 ℃, suction filtering, and drying to obtain a compound III;
(4) Under the protection of argon, adding the compound III, methanol and silica gel into a reaction bottle, heating to 50-55 ℃, adding NBS in batches, and controlling the reaction in a micro-reflux state; after NBS is added, the reaction is finished, the temperature is reduced to room temperature, methanol is removed through rotary evaporation, dichloromethane is added into residues, the residues are stirred and dispersed, filtration and leaching are carried out, filter cakes are abandoned, filtrate is dried through rotation to obtain oily crude products, and the crude products are purified through column chromatography to obtain a compound IV;
(5) Under the protection of argon, adding a compound IV and methanol into a reaction bottle, cooling to 0-5 ℃, adding sodium borohydride in batches, and controlling the process temperature to 0-15 ℃; after the reaction is finished, pouring the reaction liquid into water, adjusting the pH value to be 5-6 by hydrochloric acid, and removing methanol by rotary evaporation; then extracting with ethyl acetate, combining organic phases, washing with saturated sodium bicarbonate, drying with anhydrous sodium sulfate, removing ethyl acetate by rotary evaporation, stirring and dispersing n-heptane, performing suction filtration, and performing vacuum drying at room temperature to obtain a compound V;
(6) Under the protection of argon, adding a compound V, p-toluenesulfonic acid monohydrate and anhydrous toluene into a reaction bottle, performing reflux reaction, completely reacting, cooling, washing an organic phase with a saturated sodium bicarbonate aqueous solution to neutrality, performing rotary evaporation to remove toluene, performing negative pressure rapid column chromatography purification, adding petroleum ether after evaporation to dryness, performing dispersed crystallization at 0-5 ℃, performing suction filtration, and performing vacuum drying at room temperature to obtain a compound VI;
(7) Purging and replacing argon in a reaction bottle, then sequentially adding a compound VI, anhydrous dioxane, polyboronate pinacol ester and anhydrous potassium acetate, and then introducing an argon pipe below the liquid level for bubbling and deoxidizing; then Pd (dppf) Cl is added 2 -CH 2 Cl 2 Continuously bubbling for deoxidization; and after deoxygenation is finished, protecting the reaction system by using an argon ball, heating to the internal temperature of 85-90 ℃ for reaction, cooling after the reaction is finished, removing dioxane by rotary evaporation, adding petroleum ether, stirring and dispersing, combining petroleum ether phases, evaporating to dryness, and purifying by using column chromatography to obtain the product.
3. The method for preparing pinacol ester 2-methyl-3-phenylstyrenyl borate according to claim 2, wherein the molar ratio of 3-hydroxymethyl-2-methylbiphenyl: active manganese dioxide =1:5-10.
4. The process according to claim 2, wherein in the step (2), the molar ratio of the compound I: methyl magnesium chloride = 1.1-1.2.
5. The process according to claim 2, wherein in step (3), the molar ratio of compound II: active manganese dioxide = 1.
6. The method of claim 2, wherein in step (3), the time interval between two adjacent batches of activated manganese dioxide is 4-5 hours.
7. The method for preparing 2-methyl-3-phenylstyrylboronic pinacol ester according to claim 2, wherein in the step (4), the molar ratio of the compound III: NBS = 1-1.5.
8. The process according to claim 2, wherein in the step (5), the molar ratio of the compound IV: sodium borohydride =1, 0.5-0.55.
9. The process according to claim 2, wherein in step (6), the molar ratio of compound V: p-toluenesulfonic acid monohydrate =1, 0.1-0.3.
10. The method for preparing 2-methyl-3-phenylstyrylboronic pinacol ester according to claim 2, wherein in the step (7), the molar ratio of the compound VI: pinacol ester diborate: anhydrous potassium acetate: pd (dppf) Cl 2 -CH 2 Cl 2 ＝1:3:3:0.03。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210874329.5A CN115181120B (en) | 2022-07-22 | 2022-07-22 | Preparation method of 2-methyl-3-phenylstyryl pinacol borate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210874329.5A CN115181120B (en) | 2022-07-22 | 2022-07-22 | Preparation method of 2-methyl-3-phenylstyryl pinacol borate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115181120A true CN115181120A (en) | 2022-10-14 |
| CN115181120B CN115181120B (en) | 2024-05-28 |
Family
ID=83521586
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210874329.5A Active CN115181120B (en) | 2022-07-22 | 2022-07-22 | Preparation method of 2-methyl-3-phenylstyryl pinacol borate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115181120B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573332A (en) * | 2016-07-05 | 2018-01-12 | 广州再极医药科技有限公司 | Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application |
| CN114085184A (en) * | 2021-11-17 | 2022-02-25 | 中山大学 | Biphenyl derivative containing cyclopropane structure and preparation method and application thereof |
| CN114230512A (en) * | 2020-09-09 | 2022-03-25 | 广州再极医药科技有限公司 | Aromatic vinyl compound, preparation method thereof, intermediate, pharmaceutical composition and application thereof |
-
2022
- 2022-07-22 CN CN202210874329.5A patent/CN115181120B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573332A (en) * | 2016-07-05 | 2018-01-12 | 广州再极医药科技有限公司 | Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application |
| CN114230512A (en) * | 2020-09-09 | 2022-03-25 | 广州再极医药科技有限公司 | Aromatic vinyl compound, preparation method thereof, intermediate, pharmaceutical composition and application thereof |
| CN114085184A (en) * | 2021-11-17 | 2022-02-25 | 中山大学 | Biphenyl derivative containing cyclopropane structure and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115181120B (en) | 2024-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113999160B (en) | Preparation method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane | |
| CN110845502A (en) | Preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine | |
| WO2022012630A1 (en) | Method for synthesizing c-nucleoside compound | |
| CN104341370B (en) | Preparation method of cetilistat | |
| CN114315823B (en) | Intermediate of berberine hydrochloride and analogues thereof and preparation method thereof | |
| CN109867673B (en) | Method for synthesizing palbociclib | |
| CN103936638B (en) | The synthetic method of florfenicol | |
| CN115181120B (en) | Preparation method of 2-methyl-3-phenylstyryl pinacol borate | |
| CN116283513A (en) | Preparation method of dapagliflozin intermediate ortho-isomer impurity | |
| CN112645863B (en) | Dipyrromethene-1-ketone compound and preparation method thereof | |
| CN111269094B (en) | Preparation method of 2-bromo-1, 3-dimethoxybenzene | |
| CN111217847B (en) | Thiosilane ligand, preparation method thereof and application thereof in aryl boronization catalytic reaction | |
| CN111662147B (en) | Process for preparing diynes and analogues thereof | |
| CN103896938B (en) | A kind of preparation method of succsinic acid YM-905 | |
| CN112341433A (en) | Preparation method of loratadine | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN110981884B (en) | Method for efficiently preparing high-quality benzodifuranone | |
| CN110683992A (en) | Method for synthesizing econazole nitrate by one-pot method | |
| CN115838360B (en) | Preparation method of celecoxib | |
| CN103030580A (en) | Preparation method of lapatinib intermediate | |
| CN111377867B (en) | Intermediate for synthesizing 2- (1-alkyl-1H-pyrazol-4-yl) morpholine and preparation method and application thereof | |
| CN110016030B (en) | Preparation method of 5-fluoro-1H-pyrrole- [2,3-b ] pyridine-4-formaldehyde | |
| CN113979835B (en) | Synthesis method of pazopanib trimer impurity intermediate | |
| CN110143909B (en) | Preparation method of bilirubin intermediate | |
| CN113698392A (en) | Preparation method of Prenster intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |